The present invention relates to group A streptogramin derivatives of formula (I): 
which have advantageous antibacterial activity.
Among the known streptogramins, pristinamycin (RP 7293), an antibacterial agent of natural origin produced by Streptomyces pristinaespiralis, was isolated for the first time in 1955. The pristinamycin sold under the name Pyostacine(copyright) comprises mainly pristinamycin IIA combined with pristinamycin IA.
Another antibacterial agent of the streptogramin class, virginiamycin, was isolated from Streptomyces virginiae, ATCC 13161 [Antibiotics and Chemotherapy, 5, 632 (1955)]. Virginiamycin (Staphylomycine(copyright)) comprises mainly factor M1 (VM1) combined with factor S (VS).
The inventors have now discovered that the group A streptogramin derivatives of formula (I), wherein:
R1 is chosen from cyano and ethynyl groups,
R2 is chosen from a hydrogen atom, a methyl group, and an ethyl group, and
the bond  is a single bond (27R stereochemistry) or a double bond, have advantageous antibacterial activity, alone or when combined with at least one group B streptogramin derivative.
The streptogramin derivatives of formula (I) may be prepared, for example, by known, art-recognized methods. Such methods include reacting a 16-sulphonyloxy derivative of formula (II): 
wherein:
R2 is chosen from a hydrogen atom, a methyl group, and an ethyl group,
R3 is a perfluoroalkyl group comprising from 1 to 10 carbon atoms, and
the bond  is a single bond (27R stereochemistry) or a double bond, with an alkali metal cyanide, reducing the compound obtained from that reaction, and optionally separating the 16R and 16S isomers obtained. Another method includes carbonylating an above-defined 16-sulphonyloxy derivative of formula (II) to form a lactone, reducing the lactone to a lactol, reacting the compound formed, i.e., the lactol, with dimethyl diazomethylphosphonate or dimethyl 1-diazo-2-oxopropylphosphonate, and optionally separating the 16R and 16S isomers obtained.
In one embodiment, the R3 group is chosen from a trifluoromethyl group and a nonafluorobutyl group.
In one embodiment, the alkali metal cyanide may be chosen from potassium cyanide, sodium cyanide, and caesium cyanide.
The cyanation reaction can be carried out, for example, in the presence of a palladium derivative, for example, tetrakis(triphenylphosphine)-palladium, and copper iodide. The process can be performed, for example, in an organic solvent, such as, a nitrile (for example, acetonitrile), an ether (for example, tetrahydrofuran), an amide (for example, dimethylformamide or N-methylpyrrolidinone), at a temperature ranging, for example, from 20xc2x0 C. to the reflux temperature of the reaction mixture. The process can also be performed under an inert atmosphere, for example, argon or nitrogen.
The subsequent reduction may be carried out electrochemically, under an inert atmosphere, at a temperature of about 20xc2x0 C., working in a buffer solution, such as, a solution degassed with argon, of tetraethylammonium tetrafluoroborate, tetraethylammonium acetate and acetic acid, under a potential difference of about xe2x88x921.5 V (I=250 mA). Example 2 below gives a more detailed assessment of the operating conditions which may be used.
Such a reaction can lead to a mixture of the 16R and 16S isomers, which may be separated according to known, art-recognized methods which do not affect the rest of the molecule. For example, the separation of the epimer forms may be carried out by chromatography, such as, High Performance Liquid Chromatography (HPLC) on normal or reverse phase, HPLC on a chiral or non-chiral phase, or by flash chromatography, by crystallization, by centrifugal partition chromatography (CPC), or by any other appropriate separation technique available in the art.
The carbonylation reaction can be carried out under an atmosphere of carbon monoxide, such as, under one atmosphere, in the presence of a palladium derivative, for example, tetrakis(triphenylphosphine)-palladium, anhydrous lithium chloride and a base such as an alkali metal carbonate or alkaline-earth metal carbonate, for example, potassium carbonate, sodium carbonate, or caesium carbonate, in an inert organic solvent, such as an ether (for example, tetrahydrofuran), a nitrile (for example, acetonitrile), an amide (for example, dimethylformamide or N-methylpyrrolidinone), at a temperature ranging, for example, from 0xc2x0 C. to the reflux temperature of the reaction mixture. In one embodiment of the process, the reaction can be performed at about 20xc2x0 C.
The carbonylation reaction leads to the formation of a lactone of formula (III): 
wherein:
R2 is chosen from a hydrogen atom, a methyl group, and an ethyl group, and
the bond  is a single bond (27R stereochemistry) or a double bond.
In one embodiment, the lactone can be reduced to a lactol saturated at 16,17 and then reacted with dimethyl diazomethylphosphonate or dimethyl 1-diazo-2-oxopropylphosphonate to form an ethynyl derivative.
The reduction of the lactone to a lactol may be carried out in the presence of a hydride such as, for example, lithium or potassium tri-sec-butylborohydride (L or K Selectride), in an inert organic solvent, such as an ether (for example, tetrahydrofuran) at a temperature ranging, for example, from xe2x88x9260xc2x0 C. to 20xc2x0 C., such as, at about xe2x88x9220xc2x0 C., and under an inert atmosphere (for example, nitrogen or argon).
The reaction of dimethyl diazomethylphosphonate or dimethyl 1-diazo-2-oxopropylphosphonate can be carried out by applying the methods described by H. J. Bestmann et al., Synleft, 521 (1996) or by K. C. Nicolaou, Tetrahedron, 50(39), 11391 (1994), the relevant methods thereof are incorporated herein by reference. Such methods include a process performed in an inert solvent, such as, an ether (for example, tetrahydrofuran) or an alcohol (for example, methanol), at a temperature ranging, for example, from xe2x88x9278xc2x0 C. to 40xc2x0 C., such as, at about 20xc2x0 C. The process can be performed under an inert atmosphere (for example, argon or nitrogen).
The reaction can also lead to a mixture of the 16R and 16S isomers, which may be separated according to known, art-recognized methods which do not affect the rest of the molecule. Such methods can, for example, include chromatography, such as, High Performance Liquid Chromatography (HPLC) on normal or reverse phase, HPLC on a chiral or non-chiral phase, and flash chromatography. Crystallization, centrifugal partition chromatography (CPC), or any other appropriate separation technique available in the art can also be used.
Streptogramin derivatives of formula (II) may be obtained, for example, by reacting a fluoride or anhydride, wherein the fluoride or anhydride comprises a perfluoroalkyl group comprising 1 to 10 carbon atoms, with a streptogramin derivative of formula (IV): 
wherein:
R2 is chosen from a hydrogen atom, a methyl group, and an ethyl group, and
the bond  is a single bond (27R stereochemistry) or a double bond, in the presence of a base, such as, a tertiary amine (for example, diisopropylethylamine or triethylamine), in an inert organic solvent, such as, a chlorinated solvent (for example, dichloromethane), an ether (for example, tetrahydrofuran) or an amide (for example, dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to 20xc2x0 C., such as, at about xe2x88x9270xc2x0 C., and under an inert atmosphere (for example, argon or nitrogen).
In one embodiment, the sulphonic anhydride (for example, triflic anhydride) or the sulphonyl fluoride (for example, perfluoro-1-butanesulphonyl fluoride) corresponding to the selected R3 group can be reacted.
The pristinamycin derivatives of formula (IV) correspond, respectively, to pristinamycin IIA (PIIA), pristinamycin IIB (PIIB), pristinamycin IIC (PIIC), pristinamycin IID (PIID), pristinamycin IIF (PIIF) and pristinamycin IIG (PIIG), which are known components of natural pristinamycin. The components PIIF and PIIG have been disclosed in European patent application no. EP-A-0 614 910. Pristinamycin IIC (PIIC) and pristinamycin IID (PIID) may be obtained as described by J. C. Barrixc3xa9re et al., Expert. Opin. Invest. Drugs, 3(2),115-31 (1994).
The preparation and separation of natural group A streptogramin components, such as, streptogramins of formula (IV), can be carried out by fermentation and isolation of the constituents from the fermentation must according to or by analogy with the method described by J. Preud""homme et al., Bull. Soc. Chim. Fr., vol. 2, 585 (1968), or in European patent application no. EP-A-0 614 910. Additionally, the preparation of natural group A components may be carried out, for example, by specific fermentation, as disclosed in French patent application no. FR-A-2 689 518.
The group A streptogramin derivatives of formulae (II) and (III) are novel products that are useful for preparing streptogramin derivatives according to the invention.
The streptogramin derivatives of formula (I) may be purified, when appropriate, by physical methods, such as, crystallization, chromatography, and CPC.
The streptogramin derivatives according to the present invention have superior antibacterial properties and synergistic properties with respect to the antibacterial activity of the group B streptogramin derivatives. They are notably advantageous on account of their powerful activity, alone or in combination.
When at least one group A streptogramin derivative of the invention is combined with at least one group B streptogramin component or derivative, this component or derivative may be chosen, depending on whether it is desired to obtain a form for oral or parenteral administration, from the following natural components: pristinamycin IA, pristinamycin IB, pristinamycin IC, pristinamycin ID, pristinamycin IE, pristinamycin IF, pristinamycin IG, virginiamycin S1, S3 or S4, vernamycin B or C, etamycin or from semisynthetic derivatives as disclosed in U.S. Pat. Nos. or European patent application nos. U.S. Pat. Nos. 5,618,599, 4,798,827, 5,326,782, EP-A-0 772 630 and EP-A-0 770 132.
Representative group B streptogramin components and derivatives may include, for example, (I) streptogramin derivatives of formula (A), and salts thereof: 
wherein:
(1) Rb, Rc, Re, and Rf are each a hydrogen atom;
Rd is chosen from a hydrogen atom and a dimethylamino group; and
Ra is chosen from:
(A) xe2x80x94CH2Rxe2x80x2a groups, wherein Rxe2x80x2a is chosen from:
(i) a pyrrolidinyl-3-thio group,
(ii) a piperidyl-3-thio group,
(iii) a piperidyl-4-thio group,
wherein groups (i)-(iii) may be unsubstituted or substituted with at least one group chosen from alkyl groups, and
(iv) alkylthio groups which are substituted with 1 or 2 groups chosen from:
(a) a hydroxysulfonyl group,
(b) alkylamino groups,
(c) dialkylamino groups, which may be unsubstituted or substituted with at least one group chosen from a mercapto group or dialkylamino groups,
(d) a piperazine ring which may be substituted or unsubstituted, a morpholino group, a thiomorpholino group, a piperidino group, a 1-pyrrolidinyl group, a 2-piperidyl group, a 3-piperidyl group, a 4-piperidyl group, a 2-pyrrolidinyl group, and a 3-pyrrolidinyl group, each of which may be unsubstituted or substituted with at least one group chosen from alkyl groups, and
(B) xe2x95x90CHRxe2x80x2a groups, wherein Rxe2x80x2a is chosen from:
(i) a pyrrolidinyl-3-amino group,
(ii) a piperidyl-3-amino group and a piperidyl-4-amino group,
(iii) a pyrrolidinyl-3-oxy group,
(iv) a piperidyl-3-oxy group and a piperidyl-4-oxy group,
(v) a pyrrolidinyl-3-thio group,
(vi) a piperidyl-3-thio group and a piperidyl-4-thio group,
wherein groups (i)-(vi) may be unsubstituted or substituted with at least one group chosen from alkyl groups,
(vii) alkylamino groups,
(viii) alkyloxy groups, and
(ix) alkylthio groups,
wherein groups (vii), (viii), and (ix) are substituted with 1 or 2 groups chosen from:
(a) a hydroxysulfonyl group,
(b) alkylamino groups,
(c) dialkylamino groups unsubstituted or substituted with at least one group chosen from dialkylamino groups,
(d) trialkylammonio groups,
(e) a 4-imidazolyl group, and a 5-imidazolyl group, each of which may be unsubstituted or substituted with at least one group chosen from alkyl groups,
(f) a piperazine ring which may be substituted or unsubstituted, a morpholino group, a thiomorpholino group, a piperidino group, a 1-pyrrolidinyl group, a 2-piperidyl group, a 3-piperidyl group, a 4-piperidyl group, a 2-pyrrolidinyl group, and a 3-pyrrolidinyl group, each of unsubstituted or substituted with at least one group chosen from alkyl groups,
(C) a quinuclidinyl-3-thiomethyl group, and
(D) a quinuclidinyl-4-thiomethyl group; or
(2) Ra is a hydrogen atom, and
(a) Rb, Re, and Rf are each a hydrogen atom, and
Rd is chosen from a xe2x80x94NHCH3 group and a xe2x80x94N(CH3)2 group, and Rc is chosen from a chlorine atom and a bromine atom, or, when Rd is a xe2x80x94N(CH3)2 group, Rc is chosen from (C3-C5) alkenyl groups, or
(b) Rb, Rd, Re, and Rf are each a hydrogen atom, and
Rc is chosen from halogen atoms, aminomonoalkyl groups, aminodialkyl groups, alkyloxy groups, a trifluoromethyloxy group, thioalkyl groups, (C1-C3) alkyl groups, and trihalomethyl groups, or
(c) Rb, Rc, Re, and Rf are each a hydrogen atom, and
Rd is chosen from halogen atoms, an ethylamino group, a diethylamino group, a methylethylamino group, alkyloxy groups, a trifluoromethyloxy group, thioalkyl groups, (C1-C6) alkyl groups, aryl groups, and trihalomethyl groups, or
(d) Rb, Re, and Rf are each a hydrogen atom,
Rc is chosen from halogen atoms, aminomonoalkyl groups, aminodialkyl groups, alkyloxy groups, a trifluoromethyloxy group, thioalkyl groups, and (C1-C3) alkyl groups, and
Rd is chosen from halogen atoms, an amino group, aminomonoalkyl groups, aminodialkyl groups, alkyloxy groups, a trifluoromethyloxy group, thioalkyl groups, (C1-C6) alkyl groups, and trihalomethyl groups, or
(e) Rc, Re, and Rf are each a hydrogen atom, and
Rb and Rd are each a methyl group,
and further, for example, (II) semisynthetic group B streptogramin derivatives of formula (B), and salts thereof: 
wherein:
(A) Y is chosen from (i) a nitrogen atom and (ii) xe2x95x90CR3xe2x80x94 groups, and
(1) when Y is chosen from xe2x95x90CR3xe2x80x94 groups, R1 is chosen from
(a1) a hydrogen atom, C1-C8 alkyl groups, and C2-C8 alkenyl groups,
(b1) C3-C8 cycloalkyl groups, and saturated and unsaturated 3- to 8-membered heterocyclyl groups,
(c1) an unsubstituted phenyl group,
(d1) a phenyl group substituted with at least one substituent chosen from halogen atoms, a hydroxyl group, alkyl groups, alkyloxy groups, alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups, an amino group, alkylamino groups, and dialkylamino groups, and
(e1) groups xe2x80x94NRxe2x80x2Rxe2x80x3, wherein:
Rxe2x80x2 and Rxe2x80x3, which are identical or different, are each chosen from a hydrogen atom, and C1-C3 alkyl groups, or
Rxe2x80x2 and Rxe2x80x3, form, together with the nitrogen atom to which they are attached, a 3- to 8-membered heterocyclyl group, wherein one of the members, in addition to the nitrogen atom, may be a heteroatom chosen from an oxygen atom, a sulphur atom, and a nitrogen atom, and wherein the heterocyclyl group is unsubstituted or substituted with a group chosen from alkyl groups, C2-C8 alkenyl groups, C3-C6 cycloalkyl groups, saturated and unsaturated 4- to 6-membered heterocyclyl groups, a benzyl group, an unsubstituted phenyl group, and a substituted phenyl group, as defined above in (d1),
(f1) halomethyl groups, a hydroxymethyl group, and alkyloxymethyl groups,
(g1) alkylthiomethyl groups, wherein the alkyl portion is unsubstituted or substituted with an xe2x80x94NRxe2x80x2Rxe2x80x3 group, and wherein Rxe2x80x2 and Rxe2x80x3 are as defined above in (e1),
(h1) alkylsulphinylmethyl groups, alkylsulphonylmethyl groups, an acyloxymethyl group, a benzoyloxymethyl group, a cyclopropylaminomethyl group, and xe2x80x94(CH2)nNRxe2x80x2Rxe2x80x3 groups, wherein n is chosen from integers ranging from 1 to 4, and wherein Rxe2x80x2 and Rxe2x80x3 are as defined above in (e1), and
(i1) when R3 is a hydrogen atom, R1 is additionally chosen from a formyl group, a carboxyl group, alkyloxycarbonyl groups, and xe2x80x94CONRxe2x80x2Rxe2x80x3 groups, wherein Rxe2x80x2 and Rxe2x80x3 are defined as above in (e1), and
(2) when Y is a nitrogen atom, R1 is chosen from
(a2) options (a1), (b1), (c1), (d1), and (e1) as defined above, and
(b2) XRxc2x0 groups, wherein X is chosen from an oxygen atom, a sulphur atom, a sulphinyl group, a sulphonyl group, and an xe2x80x94NHxe2x80x94 group, and wherein Rxc2x0 is chosen from (i) (C1 to C8) alkyl groups, (ii) (C3 to C6) cycloalkyl groups, (iii) saturated and unsaturated 3- to 8-membered heterocyclyl groups, (iv) 3- to 8-membered heterocyclylmethyl groups in which the heterocyclyl portion is attached to the methyl group by a carbon atom, (v) an unsubstituted phenyl group, (vi) phenyl groups substituted with at least one group chosen from halogen atoms, a hydroxyl group, alkyl groups, alkyloxy groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, an amino group, alkylamino groups, and dialkylamino groups, (vii) xe2x80x94(CH2)nNRxe2x80x2Rxe2x80x3 groups, wherein Rxe2x80x2 and Rxe2x80x3 are as defined above in (e1), and wherein n is chosen from integers ranging from 2 to 4, and (viii) if X is an NH group, Rxc2x0 may also be a hydrogen atom;
(B) R2 is chosen from a hydrogen atom and C1-C3 alkyl groups,
(C) R3 is chosen from a hydrogen atom, alkyl groups, a carboxyl group, alkyloxycarbonyl groups, and carbamoyl groups of formula xe2x80x94COxe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are defined as above in (e1),
(D) Ra is chosen from a methyl group and an ethyl group, and
(E) Rb, Rc, and Rd are defined as follows:
(1) Rb and Rc are each a hydrogen atom, and
Rd is chosen from a hydrogen atom, a methylamino group, and a dimethylamino group, or
(2) Rb is a hydrogen atom,
Rc is chosen from a hydrogen atom, a chlorine atom, a bromine atom, and C3-C5 alkenyl groups, and
Rd is chosen from xe2x80x94N(CH3)Rxe2x80x2xe2x80x3 groups, wherein
Rxe2x80x2xe2x80x3 is chosen from
(a) alkyl groups,
(b) C2-C4 hydroxyalkyl groups,
(c) C2-C8 alkenyl groups, wherein the C2-C8 alkenyl groups are unsubstituted or substituted with (i) an unsubstituted phenyl group, (ii) a cycloalkyl(C3-C6)methyl group, (iii) an unsubstituted benzyl group, (iv) a benzyl group substituted with at least one substituent chosen from halogen atoms, a hydroxyl group, alkyl groups, alkyloxy groups, alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups, an amino group, alkylamino groups, and dialkylamino groups, or (v) heterocyclylmethyl groups and heterocyclylethyl groups, wherein the heterocyclyl portions of the heterocyclylmethyl groups and the heterocyclylethyl groups are chosen from saturated and unsaturated 5- to 6-membered heterocyclyl groups comprising from 1 to 2 heteroatoms chosen from a sulphur atom, an oxygen atom, and a nitrogen atom, and wherein the heterocyclyl groups may be unsubstituted or substituted with a group chosen from alkyl groups, C2-C8 alkenyl groups, C3-C6 cycloalkyl groups, saturated and unsaturated 4- to 6-membered heterocyclyl groups, an unsubstituted phenyl group, a benzyl group, or a substituted phenyl group as defined above in (d1),
(d) a cyanomethyl group,
(e) xe2x80x94CH2CORe groups, wherein Re is chosen from (i) xe2x80x94ORxe2x80x2e groups, wherein Rxe2x80x2e is chosen from a hydrogen atom, C1-C6 alkyl groups, C2-C6 alkenyl groups, a benzyl group, and heterocyclylmethyl groups, wherein the heterocyclyl portion is chosen from 5- to 6-membered heterocyclyl groups comprising from 1 to 2 heteroatoms chosen from a sulphur atom, an oxygen atom, and a nitrogen atom, (ii) alkylamino groups, alkylmethylamino groups, heterocyclylamino groups and heterocyclylmethylamino groups, wherein the heterocyclyl portion of the heterocyclylamino groups and the heterocyclylmethylamino groups is chosen from 5- to 6-membered saturated heterocyclyl groups comprising from 1 to 2 heteroatoms chosen from a sulphur atom, an oxygen atom, and a nitrogen atom, and wherein the heterocyclyl groups may be unsubstituted or substituted with a group chosen from alkyl groups, a benzyl group, and alkyloxycarbonyl groups, or
(3) Rb is a hydrogen atom,
Rd is chosen from an xe2x80x94NHCH3 group and an xe2x80x94N(CH3)2 group, and
Rc is chosen from a chlorine atom, and a bromine atom, and when Rd is an xe2x80x94N(CH3)2 group, Rc is chosen from C3-C5 alkenyl groups, or
(4) Rb and Rd are each a hydrogen atom, and
Rc is chosen from halogen atoms, alkylamino groups, dialkylamino groups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups, C1-C6 alkyl groups, and trihalomethyl groups, or
(5) Rb and Rc are each a hydrogen atom, and
Rd is chosen from halogen atoms, an ethylamino group, a diethylamino group, a methylethylamino group, alkyloxy groups, a trifluoromethoxy group, alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups, C1-C6 alkyl groups, a phenyl group, and trihalomethyl groups, or
(6) Rb is a hydrogen atom, and
Rc is chosen from halogen atoms, alkylamino groups, dialkylamino groups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups, and C1-C3 alkyl groups, and
Rd is chosen from halogen atoms, an amino group, alkylamino groups, dialkylamino groups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups, C1-C6 alkyl groups, and trihalomethyl groups, or
(7) Rc is a hydrogen atom, and
Rb and Rd are each a methyl group, and
even further, for example, (III) semisynthetic group B derivatives of formula (C), and salts thereof, when salts exists: 
wherein:
(A) R is chosen from
(1) xe2x80x94NR1R2 groups, wherein R1 and R2, which may be identical or different, are each chosen from
(i) a hydrogen atom,
(ii) (C1-C8) alkyl groups,
(iii) (C1-C8) alkyl groups substituted with a hydroxyl group,
(iv) (C3-C8) alkenyl groups,
(v) (C3-C8) cycloalkyl groups,
(vi) (C1-C8) alkyloxy groups,
(vii) dialkylamino groups,
(viii) phenylalkyl groups,
(ix) phenylalkyl groups substituted with at least one group chosen from halogen atoms, alkyl groups, hydroxyalkyl groups, alkyloxy groups, and dialkylamino groups, and
(x) 3- to 8-membered saturated and unsaturated heterocyclylalkyl groups comprising at least one hetero atom chosen from nitrogen, oxygen, and sulphur, or
(xi) R1 and R2 form, together with the nitrogen atom to which they are attached, a saturated, partially saturated or unsaturated mono- or polycyclic 3- to 12-membered heterocycle group, wherein one of the members, in addition to the nitrogen atom, may be an atom chosen from oxygen, sulphur, and nitrogen, and wherein the heterocyclyl group is unsubstituted or substituted with at least one group chosen from a hydroxyl group, alkyl groups, an unsubstituted phenyl group, a phenyl group substituted with a halogen atom, phenylalkyl groups, phenyl(C2-C4) alkenyl groups, hydroxyalkyl groups, acyl groups, alkyloxycarbonyl groups, heterocyclyl groups and heterocyclylcarbonyl groups, wherein the heterocyclyl portion is saturated or unsaturated (4- to 6-membered) and comprises at least one hetero atom chosen from nitrogen, sulphur, and oxygen, and
(2) xe2x80x94SR3 groups, wherein R3 is chosen from
(i) (C1-C8) alkyl groups and (C3-C8) cycloalkyl groups substituted with xe2x80x94NR1R2, wherein R1 and R2, which may be identical or different, are each chosen from a hydrogen atom and alkyl groups, or form, together with the nitrogen atom to which they are attached, a heterocycle as defined in (xi) above, and
(ii) 3- to 7-membered saturated and unsaturated heterocyclyl and heterocyclylmethyl groups, wherein one of the members, in addition to the nitrogen atom, may be a heteroatom chosen from oxygen, sulphur, and nitrogen, and wherein the heterocyclyl portion is unsubstituted or substituted with at least one group chosen from alkyl groups,
(B) 
is a residue of an unsaturated ring which is not substituted in the 5xcex3 position 
or the residue of a saturated ring which is substituted in the 5xcex3 position with a fluorine atom 
(C) Ra is chosen from a methyl group and an ethyl group, and
(D) Rb, Rc and Rd are defined below:
1) Rb and Rc are each a hydrogen atom, and Rd is chosen from a hydrogen atom, a methylamino group, and a dimethylamino group, or
2) Rb is a hydrogen atom, Rc is chosen from a hydrogen atom, a chlorine atom, a bromine atom, and a (C3 to C5) alkenyl group, and Rd is xe2x80x94N(CH3)xe2x80x94Rxe2x80x3xe2x80x2, wherein Rxe2x80x2xe2x80x3 is chosen from:
(1) alkyl groups, (2) (C2 to C4) hydroxyalkyl groups, (3) (C2 to C8) alkenyl groups, (4) phenylalkenyl groups, (5) cycloalkyl(C3 to C6)methyl groups, (6) an unsubstituted benzyl group, (7) a substituted benzyl group, (8) heterocyclylmethyl groups and heterocyclylethyl groups, (9) a xe2x80x94CH2CN group, (10) a xe2x80x94CH2COOH group, and (11) xe2x80x94CORe groups and xe2x80x94CH2CORe groups for which either:
(a) Re is xe2x80x94ORxe2x80x2e, wherein Rxe2x80x2e is chosen from a hydrogen atom, C1-C6 alkyl groups, C2-C6 alkenyl groups, a benzyl group, and heterocyclylmethyl groups, wherein the heterocyclyl portion is chosen from 5- to 6-membered heterocyclyl groups comprising from 1 to 2 heteroatoms chosen from a sulphur atom, an oxygen atom, and a nitrogen atom, or
(b) Re is chosen from alkylamino groups, alkylmethylamino groups, heterocyclylamino groups, and heterocyclylmethylamino groups, or
3) Rb is a hydrogen atom,
Rd is chosen from an xe2x80x94NHCH3 group and an xe2x80x94N(CH3)2 group, and
Rc is chosen from a chlorine atom, and a bromine atom, and when Rd is an xe2x80x94N(CH3)2 group, Rc is chosen from C3-C5 alkenyl groups, or
4) Rb and Rd are each a hydrogen atom, and
Rc is chosen from halogen atoms, alkylamino groups, dialkylamino groups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups, (C1-C6) alkyl groups, and trihalomethyl groups, or
5) Rb and Rc are each a hydrogen atom, and
Rd is chosen from halogen atoms, an ethylamino group, a diethylamino group, a methylethylamino group, alkyloxy groups, a trifluoromethoxy group, alkylthio groups, alkylsulphinyl groups, alkylsulphonyl groups, (C1-C6) alkyl groups, a phenyl group, and trihalomethyl groups, or
6) Rb is a hydrogen atom,
Rc is chosen from halogen atoms, alkylamino groups, dialkylamino groups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups, (C1-C3) alkyl groups, and
Rd is chosen from halogen atoms, an amino group, alkylamino groups, dialkylamino groups, alkyloxy groups, a trifluoromethoxy group, thioalkyl groups, (C1-C6) alkyl groups, and trihalomethyl groups, or
7) Rc is a hydrogen atom, and
Rb and Rd are each a methyl group.
It is understood that the combinations formed from the derivatives according to the invention and from group B streptogramins also fall within the context of the present invention.
The group B streptogramin derivatives of formula (B) may be prepared, for example, according to the methods disclosed in International patent application no. PCT/FR 99/00409. The group B streptogramin derivatives of formula (C) may be prepared, for example, according to the methods disclosed in International patent application no. PCT/FR 00/02146.
In vitro on Staphylococcus aureus IP8203, the streptogramin derivatives according to the invention have been shown to be active at concentrations of between 0.015 and 32 xcexcg/ml, alone or combined with a group B derivative such as pristinamycin IB. In vivo, the streptogramin derivatives according to the invention synergized the antimicrobial activity of pristinamycin IB or of semisynthetic derivatives of formula (C) on experimental infections of mice with Staphylococcus aureus IP8203 at doses ranging, for example, from 72 to 150 mg/kg orally (DC50).
The compounds according to the invention are advantageous on account of their low toxicity. None of the compounds of the invention have shown any toxicity at doses of 150 mg/kg on Staphylococcus aureus IP8203, when administered twice a day subcutaneously or orally in mice.
Representative group A streptogramin derivatives of formula (I), which may be used according to the invention, for example, include streptogramin derivatives of formula (I), wherein:
R1 is chosen from a cyano group and an ethynyl group,
R2 is a methyl group, and
the bond  is a single bond (27R stereochemistry) or a double bond, are advantageous. The compounds described below in the Examples are exemplary of such derivatives.
Representative group A streptogramin derivatives of formula (I), which may be used according to the invention, for example, include the compounds mentioned below in the examples, and the following compounds:
(16R)-16-deoxo-16-ethynylpristinamycin IIA 
(16S)-16-deoxo-16-ethynylpristinamycin IIA 
(16R)-16-cyano-16-deoxopristinamycin IIA 
(16S)-16-cyano-16-deoxopristinamycin IIA 
The examples which follow, given without any implied limitation, illustrate the present invention.
In the examples which follow, the 16-deoxopristinamycin IIA (or IIB) nomenclature indicates the replacement of the ketone function in position 16 with 2 hydrogen atoms. As the chromatography proceeded, all the fractions were analyzed by thin layer chromatography (TLC) on Merck 60F254 silica plates. The fractions corresponding to the same spot on TLC were combined and then concentrated to dryness, under reduced pressure (30xc2x0 C.; 2.7 kPa). The residues thus obtained were analyzed by known, art-recognized spectroscopic techniques (such as, NMR, IR, and MS), allowing the expected product to be identified.